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In vivo and electron microscopy were used to study the hepatocellular responses of rat livers to intravenously injected polymeric microspheres. Two microsphere preparations with different surface characteristics and degradability were used in this study. In vivo microscopy revealed that both poly(benzyl L-glutamate) (PBLG) and poly(hydroxypropyl L-glutamine) (PHPG) microspheres caused disturbance in the microcirculation of rat liver up to 2 months after injection. The observed changes included stagnant flow and adherence of white blood cells to the endothelial lining of venules an sinusoids. Kupffer cell (KC) activation following phagocytosis of microspheres was evidenced by the enlargement of KCs and increased number of KCs taking up fluorescent latex particles. Electron microscopy of rat livers revealed a wide range of hepatocellular injury associated with the administration of PBLG and PHPG microspheres. These results indicate that a small amount of remaining microspheres is sufficient to induce continuous disturbance to hepatic microcirculation and that particulate drug carriers should be designed to be rapidly degraded so that the return to normal liver function is possible.

Calcific tendinitis and rotator cuff tearing are among the most common tearing abnormalities of the rotator cuff. They are considered to be two different disease entities, but the two conditions can coexist. This study identifies the clinical and radiologic features of calcifying tendinitis in Oriental people and defines its relationship to rotator cuff tearing. From October 1989 through August 1992, there were 82 patients with calcifying tendinitis suffering from persistent shoulder pain, who received arthrographic examination. Most of the calcific depositions were located in the supraspinatus (70.7%) and infraspinatus (26.8%) tendons, and most (73.2%) were found in the critical zone. Twenty-three (28%) had arthrogrophic evidence of rotator cuff tearing, and five were confirmed by surgery. Most of the patients (77.9%) in the nontear group had an ill-defined texture, whereas in the tear group almost one half had a well-defined texture (43.5% vs 56.5%). The texture, shape of the calcific deposits, and the integrity of the rotator cuff were significantly related to the size of the calcific deposit. The presence of a calcium deposit does not rule out the possibility of a coexisting rotator cuff tear. The sex and age distribution of calcifying tendinitis in Oriental people is differnt from information reported in the Western literature., (Copyright © 1994 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Poly(benzyl L-glutamate) (PBLG) microcapsules, prepared by a solvent evaporation technique for intravenous injection, are evaluated for their potential use in diagnostic computed tomographic enhancement of liver images. The smaller microcapsules, < 3 microns, loaded with a radiopaque contrast material, ethyl iopanoate (IOPAE), produced prolonged opacification of the liver when delivered intravenously. In vivo tissue distribution studies of PBLG-131I-IOPAE (5 microCi/rat, iv) showed that liver had the highest uptake (percent of injected dose/g of tissue) among other organs 24 h postinjection. An in vitro estrogen receptor assay in pig uteri indicated that PBLG conjugated with estrone did not interfere with estrogen receptor affinity, suggesting the estrogen therapy potential of PBLG-estrone.

Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.

Clinically, pain relief is usually satisfactory after shoulder arthroplasty, but the range of motion can be limited. The changes of the lever-arms of deltoid and supraspinatus muscles are considered to be important factors influencing postoperative active motion. After excluding patients with muscle weakness resulting from a neurologic condition, patients with chronic rotator-cuff tears, patients who did not follow rehabilitation guidelines, and patients with bilateral arthroplasties, 22 arthroplasty cases remained and were evaluated. Compared with the unaffected side, four radiologic parameters were assessed: (A) offset of humeral head, (B) lateralization of humeral head, (C) acromiohumeral interval, and (D) superoinferior migration of humeral head. The differences were measured and statistically analyzed. In summary: (1) The active and passive range of motion of abduction in scapular plane were 89.5° ± 26.1° and 109.7° ± 25.0°. (2) Parameters A, B, and C statistically changed (p < 0.05). (3) B value of the operated side was reduced below zero in six (27.3%). (4) There was a tendency to create medial shifting and inferior subluxation with the arthroplasty. This had a moderate adverse correlation to the active range of motion (correlation coefficient 0.498). (5) Before normalization for bone size, only C as a single parameter had moderate correlation with motion; after normalization, this decreased. (6) If combined parameters were assessed, A + C had a moderate correlation (correlation coefficient 0.435) with motion. (7) If an accurate anatomic relationship cannot be completely restored, A seemed more significant than any other parameters (p = 0.002); namely, shoulders with a smaller offset had a more limited active range of motion in abduction., (Copyright © 1993 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Rotator cuff tear is one of the most common shoulder disorders. Most of the tears involve the critical area of the supraspinatus tendon. The rotator interval tear is extremely rare. Tear in this area is important due to its relationship with shoulder instability, different clinical symptom and different management. Recently we have uneventually treated a case with rotator interval tear after a violent throwing injury. The purpose of the paper is to emphasize the clinical differences of this unusual tear.

This study was conducted to develop a ligand for imaging estrogen-receptor-positive breast tumors by positron emission tomography or single photon emission computed tomography. We synthesized fluoro and iodo analogues of tamoxifen, and these halogenated analogues produced greater affinity for binding to the receptor than tamoxifen. Values of the inhibition affinity constants were as follows: tamoxifen, 15,000 nM; fluoromethyl-N,N-diethyltamoxifen, 2500 nM for the cis isomer and 500 nM for the trans isomer; and iodomethyl-N,N-diethyltamoxifen, 1500 nM for the cis isomer and 1000 nM for the trans isomer. In studies of human MCF7 breast tumor cell growth, concentrations that inhibited tumor growth in 50% of the cases were as follows: tamoxifen, 11 microM; fluoromethyl-N,N-diethyltamoxifen, 4.5 and 11.8 microM for the cis and trans isomers, respectively; and iodomethyl-N,N-diethyltamoxifen, 2.4 and 6.3 microM for the cis and trans isomers, respectively. These studies suggest that both fluoro and iodo analogues of tamoxifen may be useful diagnostic compounds for predicting the response of estrogen-receptor-positive breast tumors to tamoxifen analogues used in chemotherapy.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) was used to differentiate recurrent or residual malignant disease from the effects of cancer treatment. Transaxial images were obtained after injection of 5-10 mCi (185-370 MBq) of F-18 FDG in 68 patients (including 33 with brain tumors) whose posttreatment computed tomographic (CT) or magnetic resonance (MR) imaging findings had been suggestive of malignant disease. PET findings were correlated with surgical results in 18 patients and with the outcomes of CT, MR imaging, clinical, and laboratory 9-month follow-up studies in 50 patients. There was good agreement between F-18 FDG uptake and presence or absence of malignant disease except in four cases of brain tumors in which histologic findings could not be correlated with biologic behavior. The putative sensitivity and specificity in the 33 cases of brain tumors were 80% and 94%, respectively. The authors conclude that PET with F-18 FDG is useful in detection of previously treated metabolically active tumors but is limited in diagnosis of recurrent microscopic or metabolically inactive tumors.

Four intensely sweet compounds (I-IV) were obtained from the leaves of Cyclocarya paliurus (Batal.) Iljinskaya. The structure of compound I was elucidated by chemical and spectroscopic methods as 20,24-epoxy-dammarane-(3 beta,12 beta,24R)-12-O-alpha-L-rhamnopyranosyl-25- hydroxyl-3-O-alpha-(5'-O-acetyl)-L-arabinofuranoside. It is a new natural product, named cyclocarioside A, and is the main sweet principle of this plant, possessing about 200 times the sweetness intensity of sugar.

The present paper describes a quantitative determination method of tetracyclines by reversed phase high performance liquid chromatography. The method used a Waters 10 C18 4.6 nm ID x 250 nm reversed phase column, with a mobile phase composed of 14% acetonitrile-3% dimethylformamide-83% water containing 0.02 mol/L citric acid (pH-2.5), the detector wavelength was set at 350 nm, and the flow rate was maintained at 1.0 ml/min. Demethylchlortetracycline, epi-demethylchlortetracycline, demethyltetracycline, epi-demethyltetracycline, tetracycline, epi-tetracycline, chlortetracycline and epi-chlortetracycline can be separated highly efficiently. The tetracyclines and their anhydro- products can be separated on the same column with 15% acetonitrile- 15% dimethylformamide- 70% 0.02 mol/L citric acid as the mobile phase, and detected at UV 270 nm.

Diploid human fibroblasts were transfected with a plasmid carrying a v-myc oncogene linked to the neo gene or with a vector control carrying a neo gene. Drug-resistant clones were isolated and subcultured as needed. All populations went into crisis and eventually senesced. But while they were senescing, viable-appearing clones were noted among the progeny of a transfected population that expressed the v-myc oncogene. After several months, these cells began replicating more rapidly. Karyotype analysis indicated that they were clonally derived since all of them had 45 chromosomes, including 2 marker chromosomes. This cell strain was designated MSU-1.1. Similar analysis showed that cells from an earlier passage were diploid. These cells were designated MSU-1.0. Both strains have undergone more than 200 population doublings since their siblings senesced, without any change in chromosome complement. Both strains express the v-myc protein and have the same integration site for the transfected v-myc and neo genes. The MSU-1.0 cells cannot grow without exogenously added growth factors. The MSU-1.1 cells grow moderately well under the same conditions and grow to a higher saturation density than MSU-1.0 cells. Since the chance of human cells acquiring an infinite life span in culture is very rare, the data suggest that MSU-1.1 cells are derived from MSU-1.0 cells. The expression of v-myc is probably required for acquisition of an infinite life span, since this phenotype did not develop in populations not expressing this oncogene. However, expression of v-myc is clearly not sufficient, since all of the progeny of the clone that gave rise to the MSU-1.0 cells expressed this oncogene, but the vast majority of them senesced.

We describe the synthesis of new fluorotamoxifen analogues with the fluorine atom positioned on the end of the aliphatic chain of tamoxifen. The binding of fluorotamoxifens to cytosol estrogen receptors of rat uteri was determined with [3H]estradiol (5 nM). The fluorotamoxifens had similar or superior binding affinities compared with tamoxifen. The IC50 value was as follows: tamoxifen, 5 x 10(-7) M; fluorotamoxifen (VII), 5 x 10(-7) M; N,N-diethylfluorotamoxifen (IV)-cis, 1 x 10(-6) M, and trans, 2 x 10(-7) M; and (cis) fluoromethyl-N,N-diethyltamoxifen (VI) 1 x 10(-7) M. Therefore, the fluorinated tamoxifens have potential use in imaging estrogen receptors by PET.

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity via one or more metabolites. Previous studies suggested that glutathione is important for mediating NDPS-induced nephropathy. The purpose of this study was to examine the possibility that a glutathione or cysteine conjugate of NDPS or an NDPS metabolite might be the penultimate or ultimate nephrotoxic species. In one set of experiments, male Fischer 344 rats were administered intraperitoneally (i.p.) NDPS (0.4 or 1.0 mmol/kg) 1 h after pretreatment with the gamma glutamyltranspeptidase inhibitor AT-125 (acivicin) (10 mg/kg, i.p.) and renal function was monitored at 24 and 48 h. In general, AT-125 pretreatment had few effects on NDPS-induced nephropathy. In a second set of experiments, rats were treated i.p. or orally (p.o.) with a putative glutathione (S-(2-(N-(3,5-dichlorophenyl)succinimidyl)glutathione (NDPSG), a cysteine (S-(2-(N-(3,5-dichlorophenyl)succinimidyl)cysteine (NDPSC) (as the methyl ester) or N-acetylcysteine (S-(2-(N-(3,5-dichlorophenyl)succinimidyl)-N-acetylcysteine (NDPSN) conjugate of NDPS (0.2, 0.4 or 1.0 mmol/kg) or vehicle and renal function was monitored at 24 and 48 h. An intramolecular cyclization product of NDPSC, 5-carbomethoxy-2-(N-(3,5-dichlorophenyl)carbamoylmethyl)-1,4-th iazane-3-one (NDCTO) was also examined for nephrotoxic potential. None of the compounds produced toxicologically important changes in renal function or morphology. The in vitro ability of the conjugates to alter organic ion accumulation by cortical slices was also examined. All of the conjugates tested caused a reduction in p-aminohippurate (PAH) accumulation at a conjugate bath concentration of 10(-4) M, but none of the conjugates reduced tetraethylammonium (TEA) uptake. In a third experiment, the ability of the cysteine conjugate beta-lyase inhibitor aminooxyacetic acid (AOAA) (0.5 mmol/kg, i.p.) to alter the nephrotoxicity induced by two NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA) (0.2 mmol/kg, i.p.), was examined. AOAA pretreatment had no effect on NDHS- or NDHSA-induced nephrotoxicity. These results do not support a role for a glutathione or cysteine conjugate of NDPS or and NDPS metabolite as being the penultimate or ultimate nephrotoxic species.

The only ras oncogene as yet identified in cells from human fibrosarcomas is N-ras, but the relationship between N-ras oncogene expression and the malignant state of these cell lines is not known. To determine if expression of an N-ras oncogene causes human cells to become malignant, we transfected the N-ras oncogene from human leukemia cell line 8402, cloned into a high expression vector pSV N-ras, into MSU-1.1 cells, a nontumorigenic, infinite life span fibroblast cell strain with a normal morphology and a stable near-diploid karyotype. The transformants formed distinct foci composed of morphologically transformed cells. Cells from such foci expressed higher than normal levels of N-ras protein, exhibited growth factor independence, and formed large colonies in soft agar at a high frequency. Injection of progeny of these focus-derived cells s.c. into athymic mice resulted in progressively growing, invasive malignant tumors (round cell, spindle cell, or giant cell sarcomas) which reached a diameter of 6 mm in 3 to 4 weeks. Injection of focus-derived or tumor-derived cells i.v. resulted in tumors in various organs of the mice. The focus-derived cell strain tested, as well as the majority of the cells derived from the tumor it produced, exhibited the same near-diploid karyotype as the parental MSU-1.1 cells. Cells transfected with an N-ras oncogene that was expressed at a normal level formed only a single, indistinct focus, and cells from that focus were not malignant.

From 1979 to 1988, 15 cases of osteoid osteoma were diagnosed and treated at our hospital. There were 10 males and 5 females, the average age at the time of diagnosis was 17.2 years (from 5 to 54 years). The clinical features were night pain and localized pain in most cases. There was distinct pain relief by salicylate in 58% of the patients with a therapeutic trial. The duration of symptoms before diagnosis averaged 17.9 months (from 1 month to 10 years). Most of the lesions were located in the lower extremities, predominantly in the femur. The hip was a commonly affected site in children and young adults. The X-ray findings in the affected area were classical of the lesion in only 47% of the cases, therefore, preoperative localization of the nidus was aided by either tomography or CT scan. Intraoperative localization by use of an image intensifier and by taking X-rays of the excised specimen has proven to be reliable. All cases underwent en bloc resection of the lesion, and all of the patients were symptom free immediately after the operation, except for one recurrence. A second operation was performed in this case 2 years later and was successful, with pathological confirmation. Fourteen tumors were confirmed by histopathological study, one case could not be confirmed by pathological examination, however the patient obtained complete relief of symptoms postoperatively.

N-(3,5-Dichlorophenyl)succinimide (NDPS) has proven to be one of the most nephrotoxic compounds of a series of N-(halophenyl)succinimides. Previous studies in our laboratory have demonstrated that chlorine content and position on the phenyl ring are important determinants for NDPS-induced nephrotoxicity. The purpose of this study was to investigate the relationship between the electron donating or withdrawing nature of phenyl group substituents and the nephrotoxic potential of the corresponding fungicides. Rats were administered a para-substituted N-phenylsuccinimide (0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.), and renal function was monitored at 24 h and 48 h. In Sprague-Dawley rats, a clear nephrotoxicity was produced by NDPS. Weak nephrotoxicity was produced by N-(4-tert-butylphenyl)succinimide (NBPS). NDPS also was the most nephrotoxic compound in Fischer 344 rats, while weak nephrotoxicity was produced by NBPS. Lipophilic character (e.g. partition coefficient) did not correlate with acute nephrotoxicity in either rat strain. These results also indicate that there is a no correlation between the electronic nature of the phenyl substituents and resulting nephrotoxicity.

Ketamine and phencyclidine are structurally similar compounds that share many pharmacological actions, some of which are similar to the phenethylamines amphetamine and cathione. In order to integrate structural features of ketamine and cathinone, two groups of analogues, which are more conformationally restricted compared to the parent compounds, were synthesized for biological evaluation. These included 1-amino-1-methyl-2-tetralone and 2-amino-2-methyl-1-tetralone was well as several N-substituted derivatives of these molecules. Locomotor activity testing in mice revealed that 2-amino-2-methyl-1-tetralone caused an increase in locomotor activity while 1-amino-1-methyl-2-tetralone depressed spontaneous locomotor activity. None of the compounds produced hypnosis or profound ataxia.

A meniscal cyst of the knee is a rare lesion, and a palpable large meniscal cyst is even more rare. This article suggests that CT scan demonstrates clear location, size, contents, and connection of the cyst with meniscus and peripheral tissue. By a combination of arthrography and CT scan, detection of the cysts in zone 3 (parameniscal area) is possible with ample demonstration of whether the cyst is associated with a meniscal tear. This provides a guideline in determining the treatment of the lesion.

Aniline (A) and its monochlorophenyl derivatives (2-CA, 3-CA and 4-CA) are widely-used chemical intermediates. In the present study, the in vivo and in vitro nephrotoxic potential of these compounds was assessed in Fischer 344 rats. In the in vivo experiments, rats were administered a single intraperitoneal (i.p.) injection of an aniline (0.4, 1.0 or 1.5 mmol/kg) or 0.9% saline (2.0 ml/kg, i.p.), and renal function monitored at 24 and 48 h. 2-CA was the only compound tested which decreased urine volume, elevated the blood urea nitrogen (BUN) concentration and depressed both basal and lactatestimulated p-aminohippurate (PAH) accumulation by renal cortical slices at the 1.0 mmol/ kg dose. Similar results were produced following 3- and 4-CA administration, but these compounds required a dose of 1.5 mmol/kg. Aniline had little effect on renal function at the doses used in this study. In the in vitro experiments, 2-CA (10(-4) M or greater) depressed basal PAH accumulation. Tetraethylammonium (TEA) uptake was decreased by all compounds with an incubate concentration of the aniline at 10(-3) M. Lactatestimulated PAH uptake was not decreased by any test compound. These results indicate that chlorine substitution on the phenyl ring of aniline enhances nephrotoxic potential, and that 2-substitution produces the greatest increase.

Previous studies have shown that the experimental agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) produces acute nephrotoxicity via a reactive intermediate in Sprague-Dawley and Fischer-344 rats. The purpose of this study was to examine if an arene oxide intermediate is a toxic metabolite contributing to NDPS-induced nephropathy in rats. N-(3,4,5-Trichlorophenyl)succinimide (NTPS) was prepared to prevent arene oxide formation of NDPS, and its nephrotoxic potential was determined in Sprague-Dawley and Fischer-344 rats. Rats were administered a single intraperitoneal injection of NTPS (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and renal function was monitored at 24 and 48 h. NTPS (0.4 or 1.0 mmol/kg) administration produced diuresis, proteinuria, glucosuria, hematuria, decreased accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA), and increased blood urea nitrogen (BUN) and kidney weight in both strains. Extensive proximal tubular necrosis was observed in both strains of rat. The magnitude of these effects was similar to those previously reported for NDPS-induced nephrotoxicity in Sprague-Dawley and Fischer-344 rats. It was concluded that an arene oxide metabolite does not contribute to the nephrotoxic potential of NDPS. The results of the present study indicate that lipophilic character alone is not a good predictor of the nephrotoxic potential for NDPS and NTPS.

Serum C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR) were measured serially in 50 osteoarthritic patients treated with uncomplicated primary total hip arthroplasties (THAs) and also in 28 patients with painful hip for different periods after THA. The follow-up period was one year. In uncomplicated primary THA, the ESR was slightly elevated before surgery and was variable after surgery; some patients continued to have abnormally high ESRs one year after surgery. However, CRP was normal before surgery and after surgery showed a distinctive pattern that rapidly normalized within three weeks. In patients with a painful hip after THA, ESR was elevated in those with septic loosening and variable in those with mechanical loosening; however, the difference was not significant. ESR after successful revision THA was also variable. CRP was high in patients with septic loosening and normal in those with mechanical loosening. Normalization of CRP was rapid after control of infection or within three weeks of successful revision THA. Uneventful recovery after THA is indicated by normalization of CRP within three weeks, regardless of ESR. Measurement of both ESR and CRP is helpful in differentiating septic and mechanical loosening, detecting complications, and monitoring the effects of treatment, but CRP is more informative and sensitive than ESR for these purposes.

The nephrotoxic potential of N-(3,5-dichlorophenyl)succinimide (NDPS) was examined, in male Fischer-344 rats. Rats were administered NDPS (0.1, 0.2, 0.4 or 1.0 mmol/kg intraperitoneally (i.p.) or sesame oil (2.5 ml/kg, i.p.), and renal function was monitored at 24 and 48 h. NDPS (0.1 mmol/kg) stimulated organic ion uptake at 48 h. NDPS (0.2 mmol/kg) produced diuresis but did not alter blood urea nitrogen (BUN), kidney weight or organic ion uptake by renal cortical slices at 48 h. High-dose NDPS (0.4 and 1.0 mmol/kg) administration produced diuresis, decreased accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA), increased BUN and kidney weight and caused acute tubular necrosis. At 24 h, NDPS (0.2 mmol/kg) decreased uptake of PAH and TEA and tended to increase BUN. These results are similar to previous reports of NDPS-induced nephrotoxicity in Sprague-Dawley rats and suggest that either rat model would be suitable for future studies on the mechanism(s) of NDPS-induced nephropathy.

Previous studies have demonstrated that N-(3,5-dichlorophenyl)succinimide (NDCPS) is the most nephrotoxic compound among the N-(mono- or dichlorophenyl)succinimides. The purpose of this study was to examine the nephrotoxic potential of the different N-(3,5-dihalophenyl)succinimides (NDHPS) to determine the importance of the halogen species for NDHPS-induced nephrotoxicity. Male Fischer 344 rats were administered a single intraperitoneal injection of an NDHPS (0.4, 0.8, or 1.0 mmol/kg) or vehicle (2.5 ml/kg), and renal function was monitored at 24 and 48 h. NDCPS or N-(3,5-diiodophenyl)succinimide administration produced the greatest nephrotoxic response. Nephrotoxicity was characterized by diuresis, increased proteinuria, glucosuria, increased kidney weight and blood urea nitrogen (BUN) concentration, decreased accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices and proximal tubular necrosis. N-(3,5-Dibromophenyl)succinimide injection produced mild nephrotoxicity, while N-(3,5,-difluorophenyl)succinimide administration did not result in nephrotoxicity. These results indicate that the halogen species can influence the nephrotoxicity produced by the NDHPS. In addition, nephrotoxic potential did not correlate with fungicidal efficacy, which suggests that the nephrotoxic and fungicidal mechanisms of these compounds might be different.

N-(3,5-Dichlorophenyl)succinimide (NDPS), an experimental agricultural fungicide, has been shown to be a selective nephrotoxin in Sprague-Dawley and Fischer 344 rats. Previous studies have demonstrated that a toxic metabolite contributes to or is responsible for acute NDPS-induced nephrotoxicity. The purpose of this study was to investigate the role of glutathione in NDPS-induced renal effects. In 1 set of experiments, male Sprague-Dawley or Fischer 344 rats received a single intraperitoneal (i.p.) injection of NDPS (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg). Rats were killed at 1, 3, 6 or 24 h, and reduced (GSH) and oxidized (GSSG) glutathione concentrations determined in liver and renal cortex. In both rat strains NDPS (0.4 or 1.0 mmol/kg) administration produced small decreases in GSH concentrations (1 and 3 h) but moderate increases in GSSG concentrations (1 and 3 h) in liver and kidney. At 24 h both GSH and GSSG concentrations were increased, particularly in kidney. In a second set of experiments, rats were pretreated with the glutathione depletor diethyl maleate (DEM) (0.4 ml/kg, i.p.) 1 h prior to NDPS (0.2, 0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.) administration, and renal function monitored at 24 and 48 h. DEM pretreatment attenuated the increase in urine volume (24 and 48 h), proteinuria, glucosuria, hematuria and elevated blood urea nitrogen (BUN) concentration produced by NDPS (0.4 or 1.0 mmol/kg) in both Sprague-Dawley and Fischer 344 rats. NDPS-induced increases in kidney weight also were generally prevented by DEM pretreatment. Proximal tubular necrosis produced by NDPS administration was reduced by DEM but not prevented. Pretreatment with the cysteine conjugate beta-lyase inhibitor amino-oxyacetic acid (0.5 mmol/kg, i.p.) 1 h prior to NDPS (0.4 or 1.0 mmol/kg) markedly attenuated all NDPS-induced effects on renal function and morphology. These results suggest that glutathione does not play a protective role against NDPS-induced renal effects and that a glutathione or cysteine conjugate of NDPS might contribute to NDPS-induced nephrotoxicity.

The nephrotoxic potential of 3,5-dichloroaniline (DCA) was examined in male Sprague-Dawley rats. Rats were administered DCA (0.4, 0.8 or 1.0 mmol/kg, i.p.), or 0.9% saline (1.0 ml/kg, i.p.), and renal function was monitored at 24 and 48 h. DCA (0.4 mmol/kg) administration did not produce evidence of nephrotoxicity. However, DCA (0.8 mmol/kg) administration decreased urine volume and osmolality, increased proteinuria, elevated the blood urea nitrogen (BUN) concentration and decreased basal and lactate-stimulated p-aminohippurate (PAH) accumulation. Three of 4 rats receiving DCA (1.0 mmol/kg) died prior to 48 h postinjection. Incubation of renal cortical slices with DCA resulted in decreased PAH and tetraethylammonium (TEA) uptake when DCA concentrations of 10(-6) M or greater were used. These results indicate that DCA is nephrotoxic to Sprague-Dawley rats when administered in a dose of 0.8 mmol/kg or higher and is capable of altering organic ion transport in vitro.

Deuterium labelling of the succinimide ring of N-(3,5-dichlorophenyl) succinimide (NDPS) markedly reduced the acute nephrotoxicity produced by NDPS administration to Fischer 344 rats. Administration of the deuterium-labelled derivative, NDPS-d4, to male Fischer 344 rats failed to produce the marked diuresis, increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased basal p-aminohippurate (PAH) accumulation, and proximal tubular necrosis which are characteristic of NDPS-induced nephrotoxicity. However, lactate-stimulated PAH and tetraethylammonium (TEA) accumulation were decreased by NDPS-d4 (1.0 mmol/kg). The lack of nephrotoxicity produced by NDPS-d4 suggests that oxidation at the carbon-carbon bridge of the succinimide ring is an important biotransformation step in the generation of the nephrotoxic species of NDPS.

Methods for labeling the glutamate channel blocking agent MK-801 with iodine-125 (125I) and fluorine-18 (18F) are described. Radioiodine was incorporated in the 1- or 3-positions of the aromatic ring of (+/-)MK-801 by solid-state halogen exchange techniques. Attachment of the [18F]fluoromethyl group to the bridgehead methyl position was achieved by reaction of [18F]fluoride with the triflamide alcohol 8 or the novel cyclic sulfamate 9 recently reported by Merck chemists. Radiochemical yields of (+/-) 13-[18F]-fluoromethyl-MK-801 were greater than 72%, EOB; radiochemical purity greater than 99%. In competitive binding studies using rat brain homogenates, (+/-)3-bromo-MK-801 showed greater affinity than (+/-)MK-801 for the glutamate-linked channel. The experimental log P (2.1 +/- 0.1) of MK-801 is optimal for transit of the blood-brain barrier. These preliminary findings support further testing of 3-[123 I]iodo-MK-801 and (+/-)13-[18F]fluoromethyl-MK-801 as possible agents for in vivo mapping of the glutamate receptor complex.

In 1977 Kakunaga reported the carcinogen-induced transformation of the diploid human fibroblast cell line KD into focus-forming, morphologically altered cells. Cell lines were developed from 15 individual foci. These exhibited an infinite lifespan in culture and all those that were tested (7/7) formed malignant tumors (sarcomas) in athymic mice. The existing cell lines, designated HuT-11 to HuT-14, have been studied intensively during the past decade as examples of human fibroblasts malignantly transformed by treatment with a chemical carcinogen, 4-nitroquinoline-1-oxide. Recently, in comparing the HuT-11, HuT-12 and HuT-14 cell lines with KD cells, McCormick and Maher (Mutat. Res., 199, 273-291, 1988) found evidence that the malignant cells could not have been derived from the latter. But, this did not rule out the possibility that as the target cells for his original study of carcinogen-induced transformation, Kakunaga had inadvertently used cells from some other, unidentified normal individual. Since the donor of such cells would not be known and the original cell line was not available, it would be impossible to determine the degree of identity between such a target cell line and the HuT cell lines. However, in the course of examining methods for such testing, we recently became aware that the isozyme pattern of these HuT cell lines was identical to that of the human fibrosarcoma-derived cell line 8387 established in 1966. We here report that the HuT cell lines and the 8387 cell line also exhibit an identical series of HLA determinants and identical restriction fragment length polymorphisms (RFLPs). Assuming that each of these three assays measures independently inherited characteristics, the chance that an unrelated donor of the fibroblasts that gave rise to the HuT cell lines happened to possess characteristics identical to those of the patient whose fibrosarcoma gave rise to the 8387 cell line is 1 x 10(-8). Therefore, we conclude that 8387 cells are the source of the malignant cells designated HuT from Kakunaga's original transformation experiment. Additional RFLP analysis, using a probe made from M13 bacteriophage DNA which detects a hyperpolymorphic 'minisatellite' pattern in human DNA, also showed that DNA from HuT-14 cells and from 8387 cells exhibit identical banding patterns, indicating that the cell lines were taken from the same individual. The latter banding patterns differed from that observed with DNA from KD cells.(ABSTRACT TRUNCATED AT 400 WORDS)

N-(3,5-Dichlorophenyl)succinimide (NDPS) has proven to be an effective experimental agricultural fungicide. However, NDPS produces marked nephrotoxicity in Sprague-Dawley and Fischer 344 rats. The purpose of this study was to determine the importance of an intact, unsubstituted succinimide ring for acute NDPS-induced nephrotoxicity. Structural modifications included ring opening, reduction of one or both carbonyl groups, breaking the ethylene carbon-carbon bond and mono- or dialkyl substitution on the succinimide ring. Sprague-Dawley or Fischer 344 rats were administered NDPS or an NDPS analog (0.1, 0.2, 0.4, 0.8 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg, i.p.) and renal function was monitored at 24 h and 48 h. All structural modifications produced compounds with markedly reduced nephrotoxic potential in both Sprague-Dawley and Fischer 344 rats when compared to NDPS. However, N,N-diacetyl-3,5-dichloroaniline and N-(3,5-dichlorophenyl)pyrrolidine-2-one were more lethal than NDPS. The reduced renal effects of the NDPS analogs did not correlate with lipophilic character. These results indicate that an intact, unsubstituted succinimide ring is optimal for acute NDPS-induced nephrotoxicity.

Acetone has been shown to potentiate the toxicity of many halogenated hydrocarbons. The purpose of this study was to determine if acetone could alter the acute nephrotoxicity produced by the experimental fungicide N-(3,5-dichlorophenyl)succinimide (NDPS). Male Fischer 344 rats were administered acetone (1, 5 or 10 mmol/kg) or acetone vehicle (corn oil, 10 mg/kg) orally followed 16 h later by a single intraperitoneal injection of NDPS (0.2 or 0.4 mmol/kg) or NDPS vehicle (sesame oil, 2.5 ml/kg) and renal function was monitored at 24 and 48 h. Acetone (1 or 5 mmol/kg) did not alter NDPS (0.2 mmol/kg)-induced renal effects while acetone (10 mmol/kg) pretreatment attenuated NDPS (0.4 mmol/kg)-induced increases in blood urea nitrogen (BUN) concentration and kidney weight but had no effect on NDPS (0.4 mol/kg)-induced changes in urine volume or content, organic ion accumulation by renal cortical slices or renal morphology. These results suggest that acetone weakly attenuates NDPS-induced nephrotoxicity.

Cases of annoying tinnitus were selected for this observation. They were examined by general physical examination, otoscopy and some of them by audiometry and tinnitus masking patterns test, and/or Ecoch G and BSER. Two groups, TCM-WM and controls, were designed with patient's sexes, ages, severity of tinnitus almost evenly distributed. Different kinds of medicines were given to the patients of 2 groups with single blind trial. For the controls, only western medicines such as valium, nicotinic acid, mixture bromides, vitamin B Co, ATP and carbamazepine (if 100 mg of lidocaine added to 50% glucose solution intravenously was effective) were taken orally. For TCM-WM group patients, besides the drugs used above, herbal decoctions were given twice a day, and observed for 5 days per therapeutic course. The medicinal herbs consist of: Rhizoma Gastrodiae, Ramulus Uncariae cum Uncis, Poria cocos, Flos Chrysanthemi, Akebia quinata, Radix Polygoni Multiflori, Fructus Liquidambris, Radix Rehmanniae, Rhizoma Alismatis, Radix Scrophulariae, Fructus Lycii, Radix Glycyrrhizae, Semen Plantaginis and Semen Vaccariae. Of the therapeutic results in 32 cases of TCM-WM group, 11 cases (34.4%) showed absence of tinnitus, 16 (50%) improved, and 5 (15.6%) failed. The total effective rate was 84.4%. In 27 cases of the controls, 5 cases (18.6%) showed absence of tinnitus, 10 (37%) improved, and 12 (44.4%) failed. The total effective rate was 55.6%. It showed that the therapeutic results of TCM-WM group was better than those of the controls (P less than 0.05).

The experimental fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) has been shown to produce selective nephrotoxicity at least in part through the actions of one or more metabolites. The purpose of this study was to (1) determine the nephrotoxic potential of three known NDPS metabolites; N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA), and N-(3,5-dichlorophenyl)malonamic acid (DMA) and (2) examine the role of renal biotransformation in NDPS-induced nephrotoxicity. In one set of experiments, male Fischer 344 rats were administered a single intraperitoneal (ip) injection of NDPS or a NDPS metabolite (0.2, 0.4, or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg) and renal function was monitored at 24 and 48 hr. Both NDHS and NDHSA administration (0.2 or 0.4 mmol/kg) resulted in nephrotoxicity similar to that produced by NDPS (0.4 or 1.0 mmol/kg). DMA administration resulted in only minor renal effects. Addition of NDPS to renal cortical slices prepared from naive Fischer 344 rats resulted in decreases in p-aminohippurate (PAH) and tetraethylammonium (TEA) accumulation at NDPS media concentrations of 10(-4) and 10(-5) M or greater, respectively. Pretreatment of rats with microsomal enzyme activity modifiers (phenobarbital, 3-methylcholanthrene, cobalt chloride, or piperonyl butoxide) had little effect on in vitro effects of NDPS on PAH or TEA accumulation. A pattern of PAH or TEA uptake similar to that observed for NDPS was observed in vitro with NDPS-d4, a nonnephrotoxic analog of NDPS labeled on the succinimide ring with deuterium. Of the NDPS metabolites tested in vitro for nephrotoxicity, only NDHS produced decreases in PAH and TEA accumulation similar to those produced by NDPS. These results suggest that the NDPS metabolites NDHS and NDHSA are nephrotoxic compounds. However, the role of these metabolites in NDPS-induced nephrotoxicity remains to be determined. In addition, it appears that NDPS has direct effects on renal function, but these effects do not appear to be of major toxicological significance in vivo. Direct renal bioactivation of NDPS or its known metabolites to nephrotoxic species does not appear to occur in vitro.

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental agricultural fungicide which has been shown to be a selective nephrotoxin. The purpose of this study was to determine if a NDPS metabolite contributes to acute NDPS-induced nephrotoxicity. Male Sprague-Dawley or Fischer 344 rats were pretreated with a microsomal enzyme inducer [phenobarbital (PB) or 3-methylcholanthrene (3-MC)] or inhibitor [cobalt chloride (CoCl2) or piperonyl butoxide (PIBX)] followed by a single intraperitoneal injection of NDPS (0.2, 0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg). Renal function was monitored at 24 and 48 h. CoCl2 or PIBX pretreatment reduced NDPS-induced diuresis, proteinuria and hematuria, and reduced the increases seen in the blood urea nitrogen (BUN) concentration and kidney weight. NDPS-induced decreases in organic ion accumulation were not markedly altered by CoCl2 or PIBX pretreatment. PB pretreatment enhanced all NDPS- (0.2 mmol/kg) induced renal effects, while 3-MC pretreatment protected against NDPS-induced diuresis, proteinuria, hematuria, and increases in the BUN concentration observed in both rat strains. Kidney weight and organic ion uptake changes were not substantially different between NDPS-treated rats with or without 3-MC pretreatment. It was concluded that a metabolite(s) contributes to or is responsible for acute NDPS-induced nephrotoxicity and that at least 1 toxic metabolite might be of extrarenal origin.

The glutamate analogue N-methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (+/)1-iodo-MK-801 and (+/-)1-[125I]iodo-MK-801. The effect of (+/-)1-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (+/-)1-Iodo-MK-801 displaced the dissociative anesthetic ligand [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding with an IC50 of 1 microM, which is a 10-fold lower binding affinity than that of (+/-)MK-801. In in vivo autoradiographic studies, (+/-)MK-801 failed to block selective uptake of (+/-)1-iodo-MK-801 in rat brain. These results suggest that (+/-)1-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels.

The N-phenylsuccinimides are being evaluated as experimental agricultural fungicides. The purpose of this study was to examine the relationship between the electron withdrawing or electron donating properties of phenyl ring substituents on meta-substituted N-phenylsuccinimide (NPS) derivatives and the nephrotoxic potential of the corresponding fungicides. Male Fischer 344 rats were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg), and renal function monitored at 24 and 48 hr. Non-halogen-substituted NPS derivatives produced little evidence of nephrotoxicity at the doses used in this study. Among the meta-halogen derivatives of NPS, N-(3-chlorophenyl)succinimide (NCPS) was the most nephrotoxic. NCPS-induced nephrotoxicity was characterized by diuresis, proteinuria, hematuria, elevated blood urea nitrogen (BUN) concentration, decreased organic ion accumulation and proximal tubular necrosis. However, all renal effects produced by NCPS were mild to moderate. These results suggest that the electron withdrawing or donating property of a functional group is not a good predictor of the nephrotoxic potential for the corresponding fungicide. In addition, lipophilicity did not correlate with nephrotoxic potential for the meta-substituted NPS derivatives evaluated in this study.

Previous studies have shown that reducing the chlorine content of the experimental agricultural fungicide N-(3,5-dichlorophenyl)succinimide (3,5-NDPS) produces compounds with reduced nephrotoxic potential. The purpose of this study was to determine the importance of the ring position of the two chlorine atoms for the nephrotoxic potential of 3,5-NDPS in rats. Male Sprague-Dawley or Fischer 344 rats were administered a single intraperitoneal injection of a N-(dichlorophenyl)succinimide (0.4 or 1.0 mmol/kg) or vehicle (2.5 ml/kg), and renal function was monitored at 24 and 48 hr. The most nephrotoxic NDPS isomer in both rat strains was 3,5-NDPS. In Sprague-Dawley rats 2,4-, 2,5- and 3,4-NDPS were weakly nephrotoxic. In Fischer 344 rats, 2,4-NDPS (1.0 mmol/kg) and 3,5-NDPS (0.4 mmol/kg) produced similar nephrotoxicity. Weak renal effects were produced by 3,4-NDPS in Fischer 344 rats. The order of increasing nephrotoxicity did not correlate well with the increasing partition coefficients or fungicidal activities of the compounds. These results indicate that 3,5-NDPS is the most nephrotoxic NDPS isomer in rats, and that partition coefficients alone are not good predictors of nephrotoxic potential in this series. In addition, these results do not support a correlation between the fungicidal and nephrotoxic mechanisms of action of these compounds.

Azaconazole is an experimental agricultural fungicide which has shown promise for use in controlling powdery mildew on crops and bean rust. This study examined the nephrotoxic potential of a single intraperitoneal azaconazole injection (0.4 or 0.6 mmol/kg) or daily azaconazole administration (0.1 or 0.3 mmol/kg/day) for 7 days in male Fischer 344 rats. The in vitro effects of azaconazole on the accumulation of organic ions by renal cortical slices also were examined. Acute azaconazole administration (0.4 or 0.6 mmol/kg, i.p.) produced a marked decrease in urine volume at 6 h. By 48 h urine volume was still decreased in the 0.6-mmol/kg group but not the 0.4-mmol/kg group. Proteinuria (++) and slight hematuria were seen in the 0.6-mmol/kg group on both treatment days. Accumulation of p-aminohippurate (PAH) by renal cortical slices was stimulated in both azaconazole-treated groups while tetraethylammonium (TEA) accumulation was not altered. No changes in blood urea nitrogen concentration, kidney weight or renal morphology were produced at 48 h postinjection by either azaconazole dose. Daily administration of azaconazole (0.1 or 0.3 mmol/kg/day) did not significantly alter any of the renal parameters studied. Incubation of renal cortical slices with increasing concentrations of azaconazole from 10(-5) M to 10(-3) M caused a continued reduction in TEA accumulation. PAH accumulation was decreased significantly following incubation with azaconazole 10(-5) or 10(-3) M. These results indicate that azaconazole is capable of producing acute, reversible renal effects at doses equal to or less than 0.6 mmol/kg and altering organic ion transport both in vivo and in vitro. The lack of marked renal effects following exposure to azaconazole is favorable for the development of this compound as an agricultural fungicide.

The experimental fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) has been shown to be nephrotoxic in Sprague-Dawley and Fischer 344 rats. The purpose of this study was to evaluate the role of the chlorine atoms in NDPS-induced nephropathy. Male Sprague-Dawley or Fischer 344 rats received a single intraperitoneal injection of a phenylsuccinimide (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and renal function was monitored at 24 h and 48 h. In Sprague-Dawley rats urine volume was increased by NDPS and N-(3-chlorophenyl)succinimide (3-NCPS) (0.4 and 1.0 mmol/kg) at 24 h but only by NDPS at 48 h. Accumulation of both p-aminohippurate (PAH) and tetraethylammonium (TEA) was decreased only by NDPS (1.0 mmol/kg) administration. N-(2-chlorophenyl)succinimide (2-NCPS) or N-(4-chlorophenyl) succinimide (4-NCPS) (1.0 mmol/kg) administration reduced only basal and lactate-stimulated PAH accumulation. Only NDPS increased blood urea nitrogen (BUN) concentration and kidney weight. In Fischer 344 rats results were similar to those obtained in Sprague-Dawley rats, except that 3-NCPS was the only monochlorophenylsuccinimide which produced a decrease in PAH accumulation by renal cortical slices. N-Phenylsuccinimide had little effect on any renal parameter studied in either rat strain. The order of increasing nephrotoxicity generally paralleled the increasing partition. coefficients of the compounds. These results indicate that reducing the chlorine substitution of NDPS produces compounds with reduced nephrotoxic potential. In addition, lipophilic character might be a predictor for the nephrotoxic potential of N-(halophenyl)succinimides in Sprague-Dawley and Fischer 344 rats.

N-(3,5-Dichlorophenyl)succinimide (NDPS), an experimental agricultural fungicide, has been shown to produce selective nephrotoxicity in rats. Previous studies have shown that a metabolite(s) of extrarenal origin contributes to acute NDPS-induced nephrotoxicity. The purpose of this study was to determine if the organic acid transport inhibitor probenecid could modify the renal toxicity produced by NDPS administration. Male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of probenecid (60, 90 and 120 mg/kg) or 0.9% saline (1.0 ml/kg) followed 30 min later by NDPS (0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.) Renal function was monitored at 24 h and 48 h. Probenecid (60 mg/kg) did not markedly alter NDPS-induced renal effects on either post-treatment day. However, pretreatment with probenecid (90 or 120 mg/kg) blocked or attenuated the diuresis, increased proteinuria, decreased tetraethylammonium (TEA), uptake, elevation in blood urea nitrogen (BUN) concentration and increased kidney weight produced by NDPS (0.4 mmol/kg) administration. Only increased kidney weight and BUN concentration, and decreased lactate-stimulated p-aminohippurate (PAH) uptake were altered by probenecid (120 mg/kg) pretreatment when NDPS (1.0 mmol/kg) was given. NDPS-induced changes in renal morphology were not prevented by pretreatment with any probenecid dose. These results suggest that at least one nephrotoxic metabolite of NDPS is an organic acid. However, this acidic metabolite might not be the major nephrotoxic metabolite or a precursor to the major nephrotoxic metabolite(s). The identity of these metabolites remains to be determined.

Epilepsy prone rats (Jobe et al, 1982) which had previously been determined to experience relatively mild seizures in response to a sound stimulus were used in this study in order to provide a model which would reveal either proconvulsant or anticonvulsant drug activity. Animals were administered dextrorotatory (+), levorotatory (-), or racemic (+/-) ketamine hydrochloride by intravenous (tail vein) injection and subsequently challenged with a 120 db broad spectrum sound stimulus. Evaluation of drug effect was based on presence/absence of seizure, seizure severity, and convulsive latency (time from onset of stimulus to onset of convulsive episode). Potencies relative to protection against seizure susceptibility were: (+) greater than (+/-) greater than (-), with the ratio of activity of the (+) and (-) isomers comparing to the ratio of activity found by other investigators relative to other effects produced by the isomers. Of all animals which were not fully protected, there were no instances of decrement of seizure severity. At low doses, there was a slight decrease in convulsive latency, which was the only indication of a proconvulsant effect. This effect is probably prevented at the higher doses by the anticonvulsant tendency of the drug.